Field of the Invention
The present invention relates to a novel 2-phenylbenzofuran derivative or a pharmaceutically acceptable salt thereof, a production method for the same, and a pharmaceutical composition for preventing or treating an inflammatory disease comprising the same as an active ingredient
Description of the Related Art
Inflammation is a kind of defense reaction in a living body against a foreign infectious agent including a physical ⋅chemical stimulus, bacteria, fungi, virus, and various allergens. Inflammatory response is a part of innate immune response. Like in animals, the innate immune response in human starts with the macrophage's attack to a pathogen when the macrophage recognizes the pathogen as a non-self by catching a specific pattern on the cell surface of the pathogen. In the course of inflammatory response, blood plasma is accumulated in the area of inflammation to dilute the toxicity caused by bacteria, and also blood flow increases and such symptoms as erythema, pain, edema, and fever accompany.
Various biochemical phenomena are involved in the inflammatory response. In particular, it is known that nitric oxide synthase (NOS) and cyclooxygenase (COX) involved in the biosynthesis of various prostaglandins are important mediators of inflammatory response.
NOS has three isomers, which are calcium or camodulin dependent eNOS (endothelial NOS) and nNOS (neuronal NOS), and iNOS (inducible NOS) induced by bacterial endotoxin such as LPS (lipopolysaccharide) and various inflammatory cytokines such as IL-1β, TNF-α, IL-6, IL-8, and IL-12. They produce nitric oxide (NO) from L-arginine.
Nitric oxide (NO) generated by eNOS or nNOS is involved in various physiological responses including blood pressure regulation, neurotransmission, learning, and memory, indicating that NO plays an important role in maintaining homeostasis in a human body. In the meantime, NO generated by iNOS is involved in various inflammatory diseases such as arthritis, sepsis, graft rejection, autoimmune disease, and neuronal death (non-patent references 1 and 2).
LPS, one of those components forming a cell wall of gram-negative bacteria, is able to activate macrophages, due to which it is often used for an inflammatory model. Once macrophages are activated by LPS, inflammation precursors such as cytokines, chemokines, and NO are secreted, which sometimes even show a cancerous activity. The over-expressions of those inflammation mediators such as cytokines, chemokines, and NO are observed in various diseases including sepsis, rheumatoid arthritis, autoimmune disease, and diabetes. So, a substance that can regulate the inflammatory response by controlling macrophages can be an important target for the treatment of inflammatory disease.
Therefore, a substance that can suppress the over-expressions of such inflammation mediators as described above can be developed as a therapeutic agent for the treatment of inflammatory disease.
Thus, the present inventors tried to develop a compound that could suppress nitric oxide (NO), IL-6, and TNF-alpha in macrophages. In the course of our study, the present inventors confirmed that a 2-phenylbenzofuran derivative with a specific structure was excellent in suppressing NO, IL-6, and TNF alpha, and thereby confirmed that the 2-phenylbenzofuran derivative can be effectively used as a composition for preventing and treating inflammatory disease, leading to the completion of this invention.